The use of Surface Enhanced Raman Scattering (SERS) for biomolecule detection has been restricted due to the great difficulty of fabricating ultrasensitive and reproducible surface-plasmonic-resonance (SPR) substrates. Therefore, detecting extremely small amount of biomolecules for clinical application is significantly limited. In this STTR Phase II research, we propose to develop ultrasensitive (1012~1014 enhancement factors) SERS substrates with universally available Raman hot spots for well-reproducible biomolecule detection by combining optical field enhancements from both resonant photonic devices and metallic nanoentities. Compared with existing SPR substrates made by spin-coating colloidal nanoparticles or nanowire solutions, we engineer the SERS substrate using silica nanotubes coated with universally distributed silver nanoparticles, which can dramatically increase the density of the Raman scattering hot spots. We also employ highly robust Si3N4 guided-mode-resonance (GMR) gratings and resonant microcavity array to achieve even higher local electric field for SERS sensing. To link these two innovations, we will apply a highly exquisite tool---electric tweezers, to assemble the SPR-active nanotubes into the resonant photonic devices with unbeatable spatial precision of at least 150 nm. In our Phase I program, we have theoretically simulated and experimentally demonstrated SPR-active silica nanotubes with nanometer-size gaps, and detected Rhodamine 6G down to 100 fM (single-molecule level) with enhancement factors of 1.1x1010. Moreover, we fabricated Si3N4 GMR gratings using state-of-the-art nanofabrication processes and experimentally achieved ~10? enhancement factors in addition to the existing SERS effect from the SPR-active silica nanotubes. In the Phase II program, we will continue to optimize the SERS substrates for ultrahigh sensitivity up to 1012~1014 enhancement factors, improve the detection probability of ultralow concentration biomolecules in real biological samples, and apply the SERS substrates in various biomedical applications. Most of all, we will resolve potential technical challenges for product commercialization, including lowering the fabrication cost, increasing the throughput, packaging the SERS substrate with fiber-optic systems and evaluating the device reliability.